DESCRIPTION: Prostate stem cells maintain self-renewal and inhibit differentiation to remain in the stem cell state. In the prostate the mechanisms required to maintain stem cell properties can be therapeutically targeted to eliminate the stem cell compartment to reduce the number of new cells. Our long-term goal is to understand how an unregulated stem cell compartment contributes to prostatic diseases and determine if they can be a therapeutically targeted. The ABC transporters protect stem cells from xenobiotics. Prostate and hematopoietic stem cells can be enriched based on the high efflux capacity of Hoechst dye, defined as the side population. The ABC transporter ABCG2, is required for the side population phenotype. While it has long been appreciated that the side population is enriched for stem cells, and ABCG2 is required for the side population, it is unknown if ABCG2 function maintaining the stem cell state. Our data suggests ABCG2 effluxes androgen. The overall objective of this proposal is to determine whether the inhibition of ABCG2 can force accumulation of androgen resulting in stem cell differentiation. The central hypothesis is that ABCG2 efflux of androgen inhibits prostate stem cell differentiation to maintain stem cell properties. The rationale for the proposed research is to determine whether forcing prostate stem cells to differentiate is a therapeutic option for prostatic diseases that are caused by an unregulated stem cell niche including benign prostatic hyperplasia (BPH). The hypothesis is tested in three specific aims: 1. Determine the mechanism of androgen efflux to maintain stem cell properties. 2. Identify regulators of the side population phenotype that contribute to maintaining prostate stem cell properties. 3. Determine the effect of abrogated ABCG2 function on the prostate stem cell niche. The proposed studies are anticipated to demonstrate that: ABCG2 mediated androgen efflux inhibits AR induced prostate stem cell differentiation;Prostate stem cells within the side population require ABCG2 expression;and ABCG2 inhibition depletes stem cell compartment and the prostate is unable to serially regenerate. This contribution is significant because the proposed studies seek to determine whether prostate stem cells can be eliminated by inhibition of ABCG2 function. The research described in this proposal is innovative because we are functionally targeting the biology of the stem cell without the necessity of identifying prostate stem cell markers. Thus, this proposal exploits the biology of the phenotype of the prostate stem cell. PUBLIC HEALTH RELEVANCE: The research in this proposal is relevant to public health because the determining the mechanism of prostate stem cell maintenance will lead to therapeutic options to decrease the number of prostate cells to reduce symptoms of an enlarged prostate. Thus, the proposed research is relevant to part of NIH's mission that developing fundamental knowledge that will improve health and is within the NIDDK's Basic Urology Program.